1. Field of the Invention
The present invention relates to flavonoid derivatives and, more particularly, to cannabis flavonoid derivatives or the pharmaceutically acceptable salt thereof that may be used in a pharmaceutical composition for preventing and treating ocular disorders particularly glaucoma and myopia.
2. Description of the Background
Myopia or Nearsightedness, is the most common refractive error of the eye, and it has become more prevalent in recent years. About 1.6 billion people in the world suffered from myopia in 2000 and the number is expected to rise to 2.5 billion by 2020 (Francisco B M, Salvador M, Amparo N, 2015. Oxidative Stress in Myopia. Oxidative Medicine and Cellular Longevity. Vol 2015 ID: 750637). A study by the National Eye Institute (NEI) shows the prevalence of myopia grew from 25 percent of the U.S. population (ages 12 to 54) in 1971-1972 to a whopping 41.6 percent in 1999-2004. Though the exact cause for this increase in nearsightedness among Americans is unknown, many eye doctors feel it has something to do with eye fatigue from computer use and other extended near vision tasks, coupled with a genetic predisposition for myopia.
Normal and high myopia remains a major medical problem and lead to several eye pathologies such as retinal detachment, glaucoma, macular hemorrhage, cataracts and as such causes visual deterioration and eventually blindness. In an attempt to determine the genetic basis of myopia, studies have shown that a genetic variant of the BIKE (BMP2K) kinase contributes to high myopia (Liu, H. P., Lin, Y. J., Lin, W. Y., Wan, L., Sheu, J. J. C., Lin, H. J., . . . & Tsai, F. J. (2009)). A novel genetic variant of BMP2K contributes to high myopia. Journal of clinical laboratory analysis, 23(6), 362-367.), Li, Zhi-Kui. “Epidemiology, genetics and treatments for myopia. Int Journal of Ophthamology 2011, 4(6), This genetic variant has as such been identified as a potential therapeutic target for the prevention and correction of myopia,
Flavonoids are common constituents of plants and cover a wide range of functions including acting as yellow pigments in petals and leaves to attract pollinating insects. They might also appear as bluish pigments (anthocyanins) to receive certain wavelengths of light, which permits the plant to be aware of the photoperiod. Many of these flavonoids also protect the plants by being involved in the filtering of harmful ultraviolet light. Some flavonoids play crucial roles in establishing symbiotic fungi, while at the same time they fight infections caused by pathogenic fungi.
Flavonoids have relevant pharmacological activities such as; antioxidant, antidiabetic, anti-inflammatory, antiallergic, antibiotic, antidiarrheal, CNS and against cancer. In particular administration of anthocyanoside oligomer appeared to improve subjective symptoms and objective contrast sensitivity in myopia subjects (Lee, J., Lee, H. K., Kim, C. Y., Hong, Y. J., Choe, C. M., You, T. W., & Seong, G. J. (2005). Purified high-dose anthocyanoside oligomer administration improves nocturnal vision and clinical symptoms in myopia subjects. British journal of nutrition, 93(06), 895-899.).
Cannabis is credited to have several beneficial pharmacological properties. Unfortunately much attention on Cannabis is focused on its recreational use as a psychoactive drug. Studies have identified over twenty flavonoids in the Cannabis plant, such as; cannflavin A, cannflavin B, cannflavin C, chrysoeril, cosmosiin, flavocannabiside, vitexin, isovitexin, apigenin, kaempferol, myricetin, quercetin, luteolin, homoorientin and orientin (Turner, C. E., Elsohly, M. A., & Boeren, E. G., “Constituents of Cannabis Sativa . XVII., A review of the natural constituents”, Journal of Natural Products, 43(2), 169-234 (1980). The distribution of these flavonoids in the plant varies depending on the type of flavonoid. The total content of flavonoids in the Cannabis' leaves and flowers can reach 1-2.5% of its dry weight depending on environment factors and the variety of the plant.
Cannabis flavonoids have been shown to have several pharmacological properties. Apart from the specific pharmacologic properties identified, cannabis flavonoids are thought to play synergistic roles with other metabolites in the plant. For example, some flavonoids are volatile, lipophilic, permeate membranes, and seem to retain pharmacological properties in cannabis smoke (Sauer, M. A., Rifka, S. M., Hawks, R. L., Cutler, G. B., & Loriaux, D. L., “Journal of Pharmacology and Experimental Therapeutics”, 224(2), 404-407 (1983). Flavonoids may modulate the pharmacokinetics of THC, via a mechanism shared by CBD, the inhibition of P450 3A11 and P450 3A4 enzymes. These two related enzymes metabolize environmental toxins from procarcinogens to their activated forms. P450-suppressing compounds as such serve as chemoprotective agents, shielding healthy cells from the activation of benzo[α]pyrene and aflatoxin B1 (Offord, E. A., Mace, K., Avanti, O., & Pfeifer, A. M., “Mechanisms Involved In The Chemoprotective Effects Of Rosemary Extract Studied In Human Liver And Bronchial Cells”, Cancer Letters, 114(1), 275-281, (1997), which are two procarcinogenic agents found in cannabis smoke (McPartland, J. M., & Pruitt, P. L., “Alternative Therapies In Health And Medicine”, 5(4), 57 (1999). Cannabis flavonoids thus may be modulating the therapeutic effects of THC and CBDs by either synergistically enhancing desired pharmacologic effects or reducing detrimental effects.
Given the abundance of evidence supporting the health benefits of cannabis flavonoids, the present inventors have successfully synthesized rare cannabis flavonoids including cannflavin A, cannflavin B and cannflavin C, isocannflavin B and their analogs have demonstrated ability to inhibit the BMP2K kinase which has implication in the development of myopia. The present invention relates to the use of the newly synthesized flavonoids alone or in combination with other flavonoids or related bioactive compounds particularly the cannabinoids to treat or prevent ocular diseases shown to be inhibited by the use of these flavonoids and the drug combinations.